Secukinumab demonstrates high efficacy and a favourable safety profile in paediatric patients with severe chronic plaque psoriasis: 52-week results from a Phase 3 double-blind randomized, controlled trial.

BACKGROUND: Secukinumab has demonstrated sustained long-term efficacy with a favourable safety profile in various psoriatic disease manifestations in adults. OBJECTIVES: Here, the efficacy and safety of two secukinumab dosing regimens [low dose (LD) and high dose (HD)] in paediatric patients with severe chronic plaque psoriasis over one year are reported. METHODS: In this multicentre, double-blind study (NCT02471144), patients aged 6 to <18 years with severe chronic plaque psoriasis were stratified and randomized by weight (<25 kg, 25 to <50 kg, ≥50 kg) and age (6 to <12 years, 12 to <18 years) to receive low-dose (LD: 75/75/150 mg) or high-dose (HD: 75/150/300 mg) subcutaneous secukinumab or placebo or etanercept 0.8 mg/kg (up to a max of 50 mg). RESULTS: Overall, 162 patients were randomized to receive secukinumab LD (n = 40) or HD (n = 40), etanercept (n = 41) or placebo (n = 41). The co-primary objectives of the study were met with both secukinumab doses (LD and HD) showing superior efficacy compared to placebo (P < 0.0001) with respect to PASI 75 response (80.0%, 77.5% vs. 14.6%) and IGA mod 2011, 0 or 1 response (70%, 60% vs. 4.9%) at Week 12. Both secukinumab doses were superior to placebo (P < 0.0001) with respect to PASI 90 response at Week 12 (72.5%, 67.5% vs. 2.4%). The efficacy of both doses was sustained to Week 52 with secukinumab achieving higher responses vs. etanercept (PASI 75/90/100: LD, 87.5%/75.0%/40.0% and HD, 87.5%/80.0%/47.5.% vs. etanercept, 68.3%/51.2%/22.0% and IGA 0 or 1: LD, 72.5% and HD, 75.0% vs. etanercept, 56.1%). The safety profile of secukinumab was consistent with the adult Phase 3 studies, with no new safety signals identified. CONCLUSIONS: Both doses of secukinumab demonstrated high and sustained efficacy up to Week 52 with a favourable safety profile in paediatric patients with severe chronic plaque psoriasis.

Photoprotection according to skin phototype and dermatoses: practical recommendations from an expert panel.

Increasing evidence on the impact of the different wavelengths of sunlight on the skin demonstrates the need for tailored recommendations of sunscreen according to skin phototype and dermatoses, which is now possible due to advances in the filters and formulations of sunscreens. A selective literature search was performed by an international expert panel, focusing on the type of sunscreen to recommend for photoaging, skin cancers, photodermatoses, pigmentary disorders and skin inflammatory disorders. Protection against ultraviolet (UV)B is especially important for light skin as there is a high risk of sunburn, DNA damage and skin cancers. Darker skin may be naturally better protected against UVB but is more prone to hyperpigmentation induced by visible light (VL) and UVA. Protection against UVA, VL and infrared A can be helpful for all skin phototypes as they penetrate deeply and cause photoaging. Long-wave UVA1 plays a critical role in pigmentation, photoaging, skin cancer, DNA damage and photodermatoses. Adapting the formulation and texture of the sunscreen to the type of skin and dermatoses is also essential. Practical recommendations on the type of sunscreen to prescribe are provided to support the clinician in daily practice.

Adult skin acute stress responses to short-term environmental and internal aggression from exposome factors.

Exposome factors that lead to stressed skin can be defined as any disturbance to homeostasis from environmental (meteorological factors, solar radiation, pollution or tobacco smoke) and/or internal exposure (unhealthy diet, hormonal variations, lack of sleep, psychosocial stress). The clinical and biological impact of chronic exposome effects on skin functions has been extensively reviewed, whereas there is a paucity of information on the impact of short-term acute exposure. Acute stress, which would typically last minutes to hours (and generally no more than a week), provokes a transient but robust neuroendocrine-immune and tissue remodelling response in the skin and can alter the skin barrier. Firstly, we provide an overview of the biological effects of various acute stressors on six key skin functions, namely the skin physical barrier, pigmentation, defences (antioxidant, immune cell-mediated, microbial and microbiome maintenance), structure (extracellular matrix and appendages), neuroendocrine and thermoregulation functions. Secondly, we describe the biological and clinical effects on adult skin from individual exposome factors that elicit an acute stress response and their consequences in skin health maintenance. Clinical manifestations of acutely stressed skin may include dry skin that might accentuate fine lines, oily skin, sensitive skin, pruritus, erythema, pale skin, sweating, oedema and flares of inflammatory skin conditions such as acne, rosacea, atopic dermatitis, pigmentation disorders and skin superinfection such as viral reactivation. Acute stresses can also induce scalp sensitivity, telogen effluvium and worsen alopecia.

Efficacy of guselkumab in a subpopulation with pustulotic arthro-osteitis through week 52: an exploratory analysis of a phase 3, randomized, double-blind, placebo-controlled study in Japanese patients with palmoplantar pustulosis.

BACKGROUND: Previous studies of guselkumab have demonstrated clinical benefits in patients with plaque-type psoriasis, generalized pustular psoriasis, erythrodermic psoriasis and palmoplantar pustulosis (PPP). OBJECTIVE: The aim of this exploratory analysis of a double-blind, multicenter, placebo-controlled, phase 3 study in Japanese patients with PPP was to evaluate the efficacy of guselkumab in the subset of patients with pustulotic arthro-osteitis (PAO). METHODS: Patients were randomized to receive guselkumab 100 or 200 mg at weeks 0, 4, 12 and every 8 weeks, or placebo with cross-over to guselkumab 100 or 200 mg at week 16 (placebo group). Efficacy endpoints were changes from baseline in magnetic resonance imaging (MRI) score, EuroQOL-5 dimensions (EQ-5D) index score, EQ-5D pain/discomfort dimension score and C-reactive protein (CRP, mg/L) level in all PAO patients through week 52. Data from both guselkumab groups were combined and presented as results for a single overall guselkumab group. RESULTS: Among 159 patients with PPP, 66 with PAO were randomized across treatment groups. For patients with MRI data for all regions assessed, the proportion of patients in the guselkumab group with PAO characterized as severe decreased from 23.8% (10/42) at baseline to 5.4% (2/42) at week 52. The mean (SD) change from baseline at week 52 in EQ-5D index score was 0.20 (0.17) among PPP patients with PAO and 0.15 (0.17) among those without PAO in the guselkumab group. Among all PAO patients, the proportions with an EQ-5D pain/discomfort dimension score of no or slight pain/discomfort in the guselkumab group increased from baseline to week 52 [33.3% (7/21) vs. 87.5% (35/40)]. The mean (SD) CRP levels decreased in all PAO patients in the guselkumab group at week 52 compared to baseline [-1.71 (8.16) mg/L]. CONCLUSION: Guselkumab treatment showed beneficial outcomes for PAO signs and symptoms in Japanese patients with PPP.

Ixekizumab treatment improves fingernail psoriasis in patients with moderate-to-severe psoriasis: results from the randomized, controlled and open-label phases of UNCOVER-3.

BACKGROUND: Fingernail psoriasis is difficult to treat. OBJECTIVE: The objective was to evaluate the effect of ixekizumab, a monoclonal antibody selectively targeting IL-17A, on fingernail psoriasis. METHODS: This Phase 3, double-blind trial (UNCOVER-3) randomized patients to placebo, etanercept (50-mg twice weekly), or 80 mg ixekizumab as one injection every 4 (IXE Q4W) or 2 weeks (IXE Q2W) after a 160-mg starting dose. At Week 12, ixekizumab patients received open-label IXE Q4W through Week 60; placebo patients received a 160-mg starting ixekizumab dose and etanercept patients a 4-week placebo washout before starting IXE Q4W. Efficacy was assessed by mean per cent Nail Psoriasis Severity Index (NAPSI) improvement at Weeks 12 and 60. RESULTS: Of 1346 patients in the UNCOVER-3 trial, this subgroup analysis included only patients with baseline fingernail psoriasis: 116 (60.1%) placebo, 236 (61.8%) etanercept, 228 (59.1%) IXE Q4W and 229 (59.5%) IXE Q2W. At Week 12, greater mean per cent NAPSI improvements were achieved in IXE Q4W (36.7%) and IXE Q2W (35.2%) vs. placebo (-34.3%, P < 0.001 each comparison) and etanercept (20.0%, P = 0.048 vs. Q4W, P = 0.072 vs. Q2W). At Week 60, mean per cent NAPSI improvement was >80% regardless of initial treatment. At Week 12 (nonresponder imputation), complete resolution (NAPSI = 0) was achieved in 19.7% (IXE Q4W), 17.5% (IXE Q2W), 4.3% (placebo, P < 0.001 each comparison) and 10.2% (etanercept, P < 0.05 each comparison) of patients. By Week 60, >50% of patients achieved complete resolution. CONCLUSIONS: At Week 12, significant improvements in fingernail psoriasis were achieved with ixekizumab therapy. With IXE Q4W maintenance dosing, additional improvement was demonstrated through 60 weeks, and >50% of patients achieved complete resolution. Registered at clinicaltrials.gov: NCT01646177.

Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain.

OBJECTIVE: To assess the functional changes of Transient receptor potential vanilloid 1 (TRPV1) receptor and to clarify its mechanism in a rat mono-iodoacetate (MIA)-induced joint pain model (MIA rats), which has joint degeneration with cartilage loss similar to osteoarthritis. METHODS: Sensitization of TRPV1 in MIA rats was assessed by transient spontaneous pain behavior induced by capsaicin injection in knee joints and electrophysiological changes of dorsal root ganglion (DRG) neurons innervating knee joints in response to capsaicin. Mechanisms of TRPV1 sensitization were analyzed by a newly developed sandwich enzyme-linked immunosorbent assay that detects phosphorylated TRPV1, followed by functional and expression analyses of protein kinase C (PKC) in vivo and in vitro, which involves TRPV1 phosphorylation. RESULTS: Pain-related behavior induced by intra-articular injection of capsaicin was significantly increased in MIA rats compared with sham rats. In addition, capsaicin sensitivity, evaluated by capsaicin-induced inward currents, was significantly increased in DRG neurons of MIA rats. Protein levels of TRPV1 remained unchanged, but phosphorylated TRPV1 at Ser800 increased in DRG neurons of MIA rats. Phosphorylated-PKCɛ (p-PKCɛ) increased and co-localized with TRPV1 in DRG neurons of MIA rats. Capsaicin-induced pain-related behavior in MIA rats was inhibited by intra-articular pretreatment of the PKC inhibitor bisindolylmaleimide I. In addition, intra-articular injection of the PKC activator phorbol 12-myristate 13-acetate increased capsaicin-induced pain-related behavior in normal rats. CONCLUSION: TRPV1 was sensitized at the knee joint and at DRG neurons of MIA rats through PKC activation. Thus, TRPV1 sensitization might be involved in chronic pain caused by osteoarthritis.

Patient-relevant needs and treatment goals in nail psoriasis.

PURPOSE: Patient-centered health care implies that medical decisions are made jointly by physician and patient, based on patient needs. Aims were to (a) identify treatment goals for a new questionnaire on patient needs and benefits in nail psoriasis treatment; (b) analyze the importance of treatment goals in patients with nail psoriasis in general and in defined subgroups; and (c) determine the association between overall treatment goal importance and quality of life. METHODS: The study comprised the following steps: qualitative survey on needs and burdens in 120 patients; development of items by an interdisciplinary expert group; item testing in 55 patients in four countries; revision of the questionnaire and assessment in 203 patients in six countries (Germany, Denmark, Italy, Spain, USA, Japan). The percentage of patients rating the goals as 'quite/very important' was compared between various patient subgroups. RESULTS: Based on 692 free-text statements, 26 items were developed which were reduced to 24 items after pilot testing. Each of these treatment goals applied to the majority of patients in the multi-center study. Goal importance increased with severity of nail psoriasis, but not with age or disease duration. Manual dexterity and social interaction were of particular importance. Goal importance and quality of life were associated, but not redundant (r = 0.612, p < 0.001). CONCLUSIONS: Patients with nail psoriasis have manifold and specific treatment goals. Goal importance is a construct different from disease-specific quality of life and should be assessed separately. The new questionnaire can support goal setting in clinical practice.

Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA): development and validation of a tool for assessment of nail psoriasis outcomes.

BACKGROUND: Existing tools for nail psoriasis are complex and may not adequately measure outcomes that are important to patients. OBJECTIVES: We have developed and validated a new tool, the Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA), with three components: a questionnaire assessing quality of life (NAPPA-QoL), a two-part questionnaire assessing patient-relevant treatment benefits (the Patient Benefit Index, NAPPA-PBI) and a psoriasis Clinical Assessment of Severity (NAPPA-CLIN). METHODS: Development of the questionnaires involved multiple steps: (i) collection of items about nail psoriasis-related impairments and treatment goals; (ii) selection of 48 items by an expert panel, including patients; (iii) translation into eight languages; (iv) feasibility testing and (v) longitudinal validation in six countries. RESULTS: Patients found the questionnaires clear (84%) and comprehensible (95%). NAPPA-QoL and NAPPA-PBI scores correlated moderately with clinical outcomes [e.g. Nail Psoriasis Severity Index (NAPSI)] and markedly with other quality-of-life questionnaires (e.g. EQ-5D™). Both questionnaires were sensitive to change. Internal consistency was good (Cronbach α ≥ 0.88 for all scales). The NAPPA-CLIN, a brief version of NAPSI that involves assessment of only four digits rather than all 20, was found to correlate highly with total NAPSI score (r = 0.97, P < 0.001). CONCLUSIONS: Overall, the three-component NAPPA tool is a valid, reliable and practical instrument to assess patient-relevant nail psoriasis outcomes.

Attitudes and behaviors regarding sun exposure in Japan compared to Europe and North America.

The objective of our study was to assess the attitudes and behaviors in Japan regarding sun exposure and compare them to those in Europe and North America. The study population was a representative sample of individuals aged >18 years from Ipsos panels in Japan (N = 1000), North America (N = 1000), and Europe (N = 6000) using the quota method. Questionnaires covered habits, practices, and perceptions regarding sun exposure. Results revealed that the majority of people (80.1%) believed that the sun gives them energy, and 61.1% considered that being tanned made them look healthier. However, there was a significant difference between men and women regarding the appeal of tanned skin, with 54.95% of men versus 34.67% (p < 0.001) of women seeing a tan as an aesthetic asset. People aged <40 years were less likely to find a tan attractive (30.3%) compared to those aged ≥40 years (48.9%) (p < 0.001). Of those questioned, 45.70% of used sunscreen with a much higher use among women (70.10%) than men (18.74%) (p < 0.001). Almost 54% of people said they stayed in the shade to protect themselves from the sun with this behavior being more prevalent among women (67.05%) and fair-skinned individuals (56.13%). Fear of the risks of sun exposure was more common among women, with 84.8% fearing premature skin aging, compared to 71.8% of men (p < 0.001). In Japan, 44.30% of those questioned said tanned skin was attractive (p < 0.001); for Europeans and North Americans the proportions were 81.1% and 77.6%, respectively. Only a quarter (25.80%) thought it essential to return from vacation with a tan. On the other hand, Europeans showed a strong recognition of the energy the sun brings (83.18%), and widely believed that tanned skin is attractive (82.32%) and healthy (73.15%). In North America, attitudes were similar to those in Europe regarding the attractiveness of tanned skin (77.65%) and the importance of returning tanned from vacation (48.15%). Compared to Europeans and North Americans, the Japanese seemed to be more cautious about sun-induced hazards and considered lighter skin to be more attractive.

Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study.

BACKGROUND: Interleukin (IL)-17A has major proinflammatory activity in psoriatic lesional skin. OBJECTIVES: To assess the efficacy and safety of secukinumab, a fully human IgG1κ monoclonal anti-IL-17A antibody, in moderate-to-severe plaque psoriasis in a phase II regimen-finding study. METHODS: A total of 404 patients were randomized to subcutaneous placebo (n = 67) or one of three secukinumab 150 mg induction regimens: single (week 0; n = 66), early (weeks 0, 1, 2, 4; n = 133) and monthly (weeks 0, 4, 8; n = 138 patients). The primary outcome was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75) at week 12. PASI 75 responders from active treatment arms at week 12 were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24; n = 65) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed; n = 67). RESULTS: At week 12, early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54·5% and 42·0% vs. 1·5%; P < 0·001 for both). Among PASI 75 responders at week 12 entering the maintenance period, PASI 75 and PASI 90 achievement at least once from week 20 to week 28 was superior with the fixed-interval regimen [85% (n = 55) and 58% (n = 38), respectively] vs. the start-of-relapse regimen [67% (n = 45), P = 0·020, and 21% (n = 14), respectively]. Fifteen weeks after last study drug administration, < 10% of patients in the fixed-interval and start-of-relapse groups experienced a start of relapse. No immunogenicity was observed, and no injection-site reactions were reported. Reported cases of neutropenia were mild-to-moderate (≤ grade 2); none was associated with clinically significant adverse events or resulted in study discontinuation. Due to the brief duration of the safety assessment, no firm conclusions can be drawn regarding long-term safety. CONCLUSIONS: Secukinumab shows efficacy for induction and maintenance treatment of moderate-to-severe plaque psoriasis.

Stimulating peristalsis improves esophagogastric junction observation during sedated esophagogastroduodenoscopy in children and adolescents.

Background and study aims: Sedation impairs full visualization of the esophagogastric junction (EGJ) and Z line (the squamocolumnar junction) during esophagogastroduodenoscopy (EGD). The aim of this study was to determine whether induction of esophageal peristalsis could improve the ability to evaluate the Z line in children and adolescents. Patients and methods: Study 1: Consecutive patients (10-15 years) undergoing EGD with propofol or midazolam sedation were enrolled. The proportion of Z line observed was compared between the two groups. Study 2: The effect of an air infusion near the EGJ following deflation of the stomach to induce esophageal peristalsis was investigated in the patients (15-18 years), undergoing EGD with propofol sedation. The proportion of Z line observed was compared between the stimulated group and control group. Results: Study 1: 149 patients were evaluated; 87 received propofol (43 boys; average age 13.2 years (range, 10-15)) and 62 received midazolam (30 boys; average age 12.8 years (range, 10-15)). The proportion of the Z line visualized was low but was greater with propofol vs. midazolam sedation (36.8% vs 16.1%, P=0.0059). Study 2: 102 patients were evaluated; 62 had induction of peristalsis (34 boys; average age 16.2 years (range, 15-18)) and 40 controls (20 boys; average age 16.8 years (range, 15-18)). Complete visualization of the Z line achieved in 95% (59 of 62) following induction of peristalsis vs. 37.5% (15 of 40) of controls (P>0.001). Conclusions: Induction of esophageal peristalsis greatly improved visualization of the Z line during sedated EGD in children and adolescents.

The validity of the simple methods of estimating chronic subdural hematoma volume.

OBJECTIVES: It was reported that the XYZ/2 technique (using length, width and height of hematoma) is a simple and reliable method of estimation of chronic subdural hematoma volume. Two subtypes of techniques enable to adequately estimate, it is unclear which is more accurate. Computer-assisted volumetric analysis is widely considered the gold standard for CSDH volumetric analysis. It is important to consider the stability of analyses between examiners, because individual, decision-making differences may be relevant to the analysis, as hematoma margin and length are hand-operated. In this study, we investigated potential measurement biases of three neurosurgeons and analyzed the validity of the XYZ/2 technique by comparing it to the gold standard method. METHOD: We retrospectively analyzed CT scans that indicated the need for an operation in 50 patients with CSDH in our department. Three neurosurgeons measured and calculated CSDH volumes independent of one another. We investigated potential measurement biases of three neurosurgeons and analyzed the validity of the XYZ/2 technique by comparing it to the gold standard method. The XYZ/2 technique includes the "maximal method" that uses the maximum length and maximum width of a slice to determine volume, and the "central method" that uses only the central slice to measure length and width. RESULTS: ICCs for the gold standard, central method, and maximal method were 0.945, 0.916, and 0.844, respectively, all of which indicated excellent reliability. For all examiners, the differences in calculation from gold standard and central method were not statistically significant (P>0.05). The estimations of CSDH volume calculated by the maximal method were significantly greater than the estimates calculated by the gold standard (P<0.05). CONCLUSIONS: This study proves that the XYZ/2 technique is a simple and reliable method of estimating CSDH volume. The "central method" in particular yielded similar results to that of the gold standard method.

Pedunculated colorectal polyps with heads ≤ 1 cm in diameter can be resected using cold snare polypectomy.

BACKGROUND AND STUDY AIMS: Cold snare polypectomy (CSP) is not recommended for the resection of pedunculated colorectal polyp. The aim of this study was to examine the adequacy of CSP compared to hot snare polypectomy (HSP) for the complete resection of pedunculated polyps with heads ≤ 1 cm in diameter. PATIENTS AND METHODS: This was a retrospective study of a cohort of consecutive outpatients who had resection of pedunculated polyps with heads 6-10 mm in diameter using either dedicated CSP or HSP from 2014 through 2019. The primary outcome measure was occurrence of delayed bleeding. Secondary outcome measures included total procedure time, en bloc resection rate, immediate bleeding, and number of clips used. RESULTS: 415 patients with 444 eligible polyps were enrolled; the CSP group (363 patients; 386 polyps) and HSP group (52 patients; 58 polyps). Patient characteristics, polyp characteristics and en bloc resection rate were similar between groups. The mean total procedure time and mean number (range) of hemostatic clips/ patient used were significantly lower with CSP than with HSP (18± 8 min vs. 25± 9 min, P<0.001; 1.1 ± 0.6 (1-3) vs.3.1 ± 1.6 (1-5), respectively, P<0.001). Delayed bleeding occurred significantly less frequently in the CSP, 0% (0/363 vs.3.8% (2/52) in the HSP group (P<0.001), although immediate bleeding was significantly higher in CSP than HSP (84% (325/386) vs. 12% (7/58), P<0.001). CONCLUSION: Pedunculated colorectal polyps with heads ≤ 1 cm can be removed using CSP, which has several advantages over HSP.

Distal Vessel Imaging via Intra-arterial Flat Panel Detector CTA during Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Obtaining information on invisible vasculature distal to the occlusion site helps to deploy a stent retriever safely during mechanical thrombectomy for large-vessel occlusion. It is essential to reduce the amount of contrast used for detecting the vessels distal to the occlusion site because acute ischemic stroke patients tend to have chronic kidney disease and patients with severe chronic kidney disease are at an increased risk of contrast-associated acute kidney injury. We assessed whether vessels distal to the occlusion site during acute ischemic stroke with large-vessel occlusion could be visualized on angiographic images using flat panel detector CT acquired following intra-arterial diluted contrast injection, compared with MRA findings. MATERIALS AND METHODS: Between May 2019 and January 2020, we enrolled 28 consecutive patients with large-vessel occlusions of the anterior circulation eligible for mechanical thrombectomy following MR imaging. The patients underwent CBV imaging using flat panel detector CT with an intra-arterial diluted contrast injection instead of intravenous injection. Flat panel detector CT angiographic images reconstructed from the same dataset were evaluated for image quality, collateral status of the MCA territory, and visualization of the vessels distal to the occlusion site. These findings were compared with MRA findings. RESULTS: Twenty-two patients were retrospectively examined. Flat panel detector CT angiographic image quality in 20 patients (91%) was excellent or good. The distal portion of the occluded vessel segment was visualized in 14 patients (70%), while the proximal portion of the segment adjacent to the occluded vessel in 3 (15%) was visualized. No visualization was observed in only 1 patient (5%) with no collateral supply. Flat panel detector CT angiographic images were shown to evaluate vessels distal to the occlusion site more accurately than MRA. CONCLUSIONS: In acute ischemic stroke with large-vessel occlusion, flat panel detector CT angiographic images could successfully visualize vessels distal to the occlusion site with a small amount of contrast material.

Positive selection of gamma delta CTL by TL antigen expressed in the thymus.

To elucidate the funciton of the mouse TL antigen in the thymus, we have derived two TL transgenic mouse strains by introducing Tl alpha 2-3 of A strain origin with its own promoter onto a C3H background with no expression of TL in the thymus. These transgenic mouse strains, both of which express high levels of Tla2-3-TL antigen in their thymus, were analyzed for their T cell function with emphasis on cytotoxic T lymphocyte (CTL) generation. A T cell response against TL was induced in Tg. Tla2-3-1, Tg. Tla2-3-2, and control C3H mice by skin grafts from H-2Kb/T3b transgenic mice, Tg.Con.3-1, expressing T3b-TL ubiquitously. Spleen cells from mice that had rejected the T3b-TL positive skin grafts were restimulated in vitro with Tg. Con.3-1 irradiated spleen cells. In mixed lymphocyte cultures (MLC), approximately 20% and 15% of Thy-1+ T cells derived from Tg.Tla2-3-1 and Tg.Tla2-3-2, respectively, expressed TCR gamma delta, whereas almost all those from C3H expressed TCR alpha beta. The MLC from Tg. Tla2-3-2 and C3H demonstrated high CTL activity against TL, while those from Tg. Tla2-3-1 had little or none. The generation of gamma delta CTL recognizing TL in Tg. Tla2-3-2, but not C3H mice, was confirmed by the establishment of CTL clones. A total of 14 gamma delta CTL clones were established from Tg. Tla2-3-2, whereas none were obtained from C3H. Of the 14 gamma delta CTL clones, 8 were CD8+ and 6 were CD4-CD8- double negative. The CTL activity of all these clones was TL specific and inhibited by anti-TL, but not by anti-H-2 antibodies, demonstrating that they recognize TL directly without antigen presentation by H-2. The CTL activity was blocked by antibodies to TCR gamma delta and CD3, and also by antibodies to CD 8 alpha and CD8 beta in CD8+ clones, showing that the activity was mediated by TCR gamma delta and coreceptors. The thymic origin of these gamma delta CTL clones was indicated by the expression of Thy-1 and Ly-1 (CD5), and also CD8 alpha beta heterodimers in CD8+ clones on their surfaces and by the usage of TCR V gamma 4 chains in 12 of the 14 clones. Taken together, these results suggest that Tla2-3-TL antigen expressed in the thymus engages in positive selection of a sizable population of gamma delta T cells.